PTCOG Gastrointestinal Subcommittee Lower Gastrointestinal Tract Malignancies Consensus Statement.

Purpose: Radiotherapy delivery in the definitive management of lower gastrointestinal (LGI) tract malignancies is associated with substantial risk of acute and late gastrointestinal (GI), genitourinary, dermatologic, and hematologic toxicities. Advanced radiation therapy techniques such as proton beam therapy (PBT) offer optimal dosimetric sparing of critical organs at risk, achieving a more favorable therapeutic ratio compared with photon therapy. Materials and Methods: The international Particle Therapy Cooperative Group GI Subcommittee conducted a systematic literature review, from which consensus recommendations were developed on the application of PBT for LGI malignancies. Results: Eleven recommendations on clinical indications for which PBT should be considered are presented with supporting literature, and each recommendation was assessed for level of evidence and strength of recommendation. Detailed technical guidelines pertaining to simulation, treatment planning and delivery, and image guidance are also provided. Conclusion: PBT may be of significant value in select patients with LGI malignancies. Additional clinical data are needed to further elucidate the potential benefits of PBT for patients with anal cancer and rectal cancer.

SMAD4 loss predicts worse overall and distant metastasis-free survival in patients with resected pancreatic adenocarcinoma.

BACKGROUND: In select patients, pancreatic adenocarcinoma remains a local disease, yet there are no validated biomarkers to predict this behavior and who may benefit from aggressive local treatments. This study sought to determine if SMAD4 (mothers against decapentaplegic homolog 4) messenger RNA-sequencing (RNA-seq) expression is a robust method for predicting overall survival (OS) and distant metastasis-free survival (DMFS) in patients with resected pancreatic adenocarcinoma. METHODS: Utilizing The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), 322 patients with resected stage I-III pancreatic adenocarcinoma were identified. In TCGA, multivariable proportional hazards models were used to determine the association of SMAD4 genomic aberrations and RNA-seq expression with OS and DMFS. In the ICGC, analysis sought to confirm the predictive performance of RNA-seq via multivariable models and receiver operator characteristic curves. RESULTS: In TCGA, the presence of SMAD4 genomic aberrations was associated with worse OS (hazard ratio [HR], 1.55; 95% CI, 1.00-2.40; p = .048) but not DMFS (HR, 1.33; 95% CI, .87-2.03; p = .19). Low SMAD4 RNA-seq expression was associated with worse OS (HR, 1.83; 95% CI, 1.17-2.86; p = .008) and DMFS (HR, 1.70; 95% CI, 1.14-2.54; p = .009). In the ICGC, increased SMAD4 RNA-seq expression correlated with improved OS (area under the curve [AUC], .92; 95% CI, .86-.94) and DMFS (AUC, .84; 95% CI, .82-.87). CONCLUSIONS: In patients with resected pancreatic adenocarcinoma, SMAD4 genomic aberrations are associated with worse OS but do not predict for DMFS. Increased SMAD4 RNA-seq expression is associated with improved OS and DMFS in patients with resected pancreatic adenocarcinoma. This reproducible finding suggests SMAD4 RNA-seq expression may be a useful marker to predict metastatic spread.

Radiation dose is associated with improved local control for large, but not small, hepatocellular carcinomas.

BACKGROUND: With advances in understanding liver tolerance, conformal techniques, image guidance, and motion management, dose-escalated radiotherapy has become a potential treatment for inoperable hepatocellular carcinoma (HCC). We aimed to evaluate the possible impact of biologically effective dose (BED) on local control and toxicity among patients with HCC. METHODS AND MATERIALS: Patients treated at our institution from 2009 to 2018 were included in this retrospective analysis if they received definitive-intent radiotherapy with a nominal BED of at least 60 Gy. Patients were stratified into small and large tumors using a cutoff of 5 cm, based on our clinical practice. Toxicity was assessed using ALBI scores and rates of clinical liver function deterioration. RESULTS: One hundred and twenty-eight patients were included, with a mean follow-up of 16 months. The majority of patients (90.5%) had a good performance status (ECOG 0-1), with Child-Pugh A (66.4%) and ALBI Grade 2 liver function at baseline (55.4%). Twenty (15.6%) patients had a local recurrence in the irradiated field during the follow-up period. Univariate and multivariate Cox proportional hazard analyses showed that only BED significantly predicted local tumor recurrence. Higher BED was associated with improved local control in tumors with equivalent diameters over 5 cm but not in smaller tumors. There was no difference in liver toxicity between the low and high-dose groups. CONCLUSIONS: Higher radiotherapy dose is associated with improved local control in large tumors but not in tumors smaller than 5 cm in diameter. High-dose radiotherapy was not associated with increased liver toxicity.

Considering Lumpectomy Cavity PTV Expansions: Characterization of Intrafraction Lumpectomy Cavity Motion.

PURPOSE: Accelerated partial breast irradiation and lumpectomy cavity boost radiation therapy plans generally use volumetric expansions from the lumpectomy cavity clinical target volume to the planning target volume (PTV) of 1 to 1.5 cm, substantially increasing the volume of irradiated breast tissue. The purpose of this study was to quantify intrafraction lumpectomy cavity motion during external beam radiation therapy to inform the indicated clinical target volume to PTV expansion. METHODS AND MATERIALS: Forty-four patients were treated with a whole breast irradiation using traditional linear accelerator-based radiation therapy followed by lumpectomy cavity boost using magnetic resonance (MR)-guided radiation therapy on a prospective registry study. Two-dimensional cine-MR images through the center of the surgical cavity were acquired during each boost treatment to define the treatment position of the lumpectomy cavity. This was compared with the reference position to quantify intrafraction cavity motion. Free-breathing technique was used during treatment. Clinical outcomes including toxicity, cosmesis, and rates of local control were additionally analyzed. RESULTS: The mean maximum displacement per fraction in the anterior-posterior (AP) direction was 1.4 mm. Per frame, AP motion was <5 mm in 92% of frames. The mean maximum displacement per fraction in the superior-inferior (SI) direction was 1.2 mm. Per frame, SI motion was <5 mm in 94% of frames. Composite motion was <5 mm in 89% of frames. Three-year local control was 97%. Eight women (18%) developed acute G2 radiation dermatitis. With a median follow-up of 32.4 months, cosmetic outcomes were excellent (22/44, 50%), good (19/44, 43%), and fair (2/44, 5%). CONCLUSIONS: In approximately 90% of analyzed frames, intrafraction displacement of the lumpectomy cavity was <5 mm, with even less motion expected with deep inspiratory breath hold. Our results suggest reduced PTV expansions of 5 mm would be sufficient to account for lumpectomy cavity position, which may accordingly reduce late toxicity and improve cosmetic outcomes.

Interpretable machine learning for predicting pathologic complete response in patients treated with chemoradiation therapy for rectal adenocarcinoma.

Purpose: Pathologic complete response (pCR) is a critical factor in determining whether patients with rectal cancer (RC) should have surgery after neoadjuvant chemoradiotherapy (nCRT). Currently, a pathologist's histological analysis of surgical specimens is necessary for a reliable assessment of pCR. Machine learning (ML) algorithms have the potential to be a non-invasive way for identifying appropriate candidates for non-operative therapy. However, these ML models' interpretability remains challenging. We propose using explainable boosting machine (EBM) to predict the pCR of RC patients following nCRT. Methods: A total of 296 features were extracted, including clinical parameters (CPs), dose-volume histogram (DVH) parameters from gross tumor volume (GTV) and organs-at-risk, and radiomics (R) and dosiomics (D) features from GTV. R and D features were subcategorized into shape (S), first-order (L1), second-order (L2), and higher-order (L3) local texture features. Multi-view analysis was employed to determine the best set of input feature categories. Boruta was used to select all-relevant features for each input dataset. ML models were trained on 180 cases from our institution, with 37 cases from RTOG 0822 clinical trial serving as the independent dataset for model validation. The performance of EBM in predicting pCR on the test dataset was evaluated using ROC AUC and compared with that of three state-of-the-art black-box models: extreme gradient boosting (XGB), random forest (RF) and support vector machine (SVM). The predictions of all black-box models were interpreted using Shapley additive explanations. Results: The best input feature categories were CP+DVH+S+R_L1+R_L2 for all models, from which Boruta-selected features enabled the EBM, XGB, RF, and SVM models to attain the AUCs of 0.820, 0.828, 0.828, and 0.774, respectively. Although EBM did not achieve the best performance, it provided the best capability for identifying critical turning points in response scores at distinct feature values, revealing that the bladder with maximum dose >50 Gy, and the tumor with maximum2DDiameterColumn >80 mm, elongation <0.55, leastAxisLength >50 mm and lower variance of CT intensities were associated with unfavorable outcomes. Conclusions: EBM has the potential to enhance the physician's ability to evaluate an ML-based prediction of pCR and has implications for selecting patients for a "watchful waiting" strategy to RC therapy.

Acute toxicity in patients treated with concurrent chemoradiotherapy with proton versus intensity-modulated radiation therapy for nonmetastatic head and neck cancers.

BACKGROUND: We evaluated if proton therapy is associated with decreased acute toxicities compared to intensity-modulated radiation therapy (IMRT) in patients receiving concurrent chemoradiotherapy for head and neck cancers. METHODS: We analyzed 580 patients with nonmetastatic head and neck cancers. Primary endpoint was any 90-day grade ≥3 toxicity, prospectively collected and graded per CTCAEv4. Modified Poisson regression models were used. RESULTS: Ninety-five patients received proton and 485 IMRT. The proton group had more HPV-positive tumors (65.6 vs. 58.0%, p = 0.049), postoperative treatment (76.8 vs. 62.1%, p = 0.008), unilateral neck treatment (18.9 vs. 6.6%, p < 0.001) and significantly lower doses to organs-at-risk compared to IMRT group. Adjusted for patient and treatment characteristics, the proton group had decreased grade 2 dysgeusia (RR0.67, 95%CI 0.53-0.84, p = 0.004) and a trend toward lower grade ≥3 toxicities (RR0.60, 95%CI 0.41-0.88, p = 0.06). CONCLUSIONS: Proton therapy was associated with significantly reduced grade 2 dysgeusia and nonstatistically significant decrease in acute grade ≥3 toxicities compared to IMRT.

Activity Monitoring for Toxicity Detection and Management in Patients Undergoing Chemoradiation for Gastrointestinal Malignancies.

PURPOSE: Physical activity is associated with decreased hospitalization during cancer treatment. We hypothesize that activity data can help identify and triage high-risk patients with GI cancer undergoing concurrent chemoradiation. MATERIALS AND METHODS: This prospective study randomly assigned patients to activity monitoring versus observation. In the intervention arm, a 20% decrease in daily steps or 20% increase in heart rate triggered triage visits to provide supportive care, medication changes, and escalation of care. In the observation group, activity data were recorded but not monitored. The primary objective was to show a 20% increase in triage visits in the intervention group. Secondary objectives were estimating the rates of emergency department (ED) visits and hospitalizations. Crude and adjusted odds ratios were computed using logistic regression modeling. RESULTS: There were 22 patients in the intervention and 18 in the observation group. Baseline patient and treatment characteristics were similar. The primary objective was met, with 3.4 more triage visits in the intervention group than in the observation group (95% CI, 2.10 to 5.50; P < .0001). Twenty-six (65.0%) patients required at least one triage visit, with a higher rate in the intervention arm compared with that in the observation arm (86.4% v 38.9%; odds ratio, 9.95; 95% CI, 2.13 to 46.56; P = .004). There was no statistically significant difference in ED visit (9.1% v 22.2%; P = .38) or hospitalization (4.5% v 16.7%; P = .31). CONCLUSION: It is feasible to use activity data to trigger triage visits for symptom management. Further studies are investigating whether automated activity monitoring can assist with early outpatient management to decrease ED visits and hospitalizations.

Quantifying the impact of the COVID-19 pandemic on gastrointestinal cancer care delivery.

BACKGROUND AND AIM: This study quantifies how changes in healthcare utilization and delivery during the first months of the COVID-19 pandemic have altered the presentation, treatment, and management of patients with gastrointestinal (GI) malignancies within an academic health system. METHODS AND RESULTS: Patients diagnosed with a GI malignancy (ICD10: C15-C26) who received medical care within the health system during the observation period (first 44 weeks of 2019 and 2020) were identified for a retrospective cohort study. Deidentified patient encounter parameters were collected for this observation period and separated into pre-pandemic (weeks 1-10) and early pandemic (weeks 11-20) study periods. Difference-in-difference analyses adjusted for week-specific and year-specific effects quantified the impact of the COVID-19 pandemic on care delivery between pre-pandemic and early pandemic study periods in 2020. Across all GI malignancies, the COVID-19 pandemic has been associated with a significant decline in the number of patients with new patient visits (NPVs) (p = 1.2 × 10-4 ), Radiology encounters (p = 1.9 × 10-7 ), Surgery encounters (p = 1.6 × 10-3 ), Radiation Oncology encounters (p = 4.1 × 10-3 ), and infusion visits (6.1 × 10-5 ). Subgroup analyses revealed cancer-specific variations in changes to delivery. Patients with colorectal cancer (CRC) had the most significant decrease in NPVs (p = 7.1 × 10-5 ), which was significantly associated with a concomitant decrease in colonoscopies performed during the early pandemic period (r2  = 0.722, p = 2.1 × 10-10 ). CONCLUSIONS: The COVID-19 pandemic has been associated with significant disruptions to care delivery. While these effects were appreciated broadly across GI malignancies, CRC, diagnosed and managed by periodic screening, has been affected most acutely.

Multi-institutional Comparison of Intensity Modulated Photon Versus Proton Radiation Therapy in the Management of Squamous Cell Carcinoma of the Anus.

PURPOSE: Concurrent chemoradiation therapy is a curative treatment for squamous cell carcinoma of the anus, but patients can suffer from significant treatment-related toxicities. This study was undertaken to determine whether intensity modulated proton therapy (IMPT) is associated with less acute toxicity than intensity modulated radiation therapy (IMRT) using photons. MATERIALS AND METHODS: We performed a multi-institutional retrospective study comparing toxicity and oncologic outcomes of IMRT versus IMPT. Patients with stage I-IV (for positive infrarenal para-aortic or common iliac nodes only) squamous cell carcinoma of the anus, as defined by the American Joint Committee on Cancer's AJCC Staging Manual, eighth edition, were included. Patients with nonsquamous histology or mixed IMPT and IMRT treatment courses were excluded. Acute nonhematologic toxicities, per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4, were recorded prospectively at all sites. Acute and late toxicities, dose metrics, and oncologic outcomes were compared between IMRT and IMPT using univariable and multivariable statistical methods. To improve the robustness of our analysis, we also analyzed the data using propensity score weighting methods. RESULTS: A total of 208 patients were treated with either IMPT (58 patients) or IMRT (150 patients). Of the 208 total patients, 13% had stage I disease, 36% stage II, 50% stage III, and 1% stage IV. IMPT reduced the volume of normal tissue receiving low-dose radiation but not high-dose radiation to bladder and bowel. There was no significant difference between treatment groups in overall grade 3 or greater acute toxicity (IMRT, 68%; IMPT, 67%; P = .96) or 2-year overall grade 3 or greater late toxicity (IMRT, 3.5%; IMPT, 1.8%; P = .88). There was no significant difference in 2-year progression-free survival (hazard ratio, 0.8; 95% CI, 0.3-2.0). CONCLUSIONS: Despite reducing the volume of normal tissue receiving low-dose radiation, IMPT was not associated with decreased grade 3 or greater acute toxicity as measured by CTCAE. Additional follow-up is needed to assess whether important differences arise in late toxicities and if further prospective evaluation is warranted.

Concurrent Nab-paclitaxel and Radiotherapy: Novel Radiosensitization for Borderline Resectable or Unresectable Pancreatic Cancer.

PURPOSE: This study evaluates the toxicity and tumor response with concurrent nab-paclitaxel chemoradiotherapy (CRT) compared with standard (5-fluorouracil or gemcitabine) CRT. MATERIALS AND METHODS: Fifty patients with borderline resectable or unresectable pancreatic adenocarcinoma from 2014 to 2017 were divided into 2 groups: concurrent nab-paclitaxel (100 to 125 mg/m2 weekly) CRT (median: 2.1 Gy fraction size and 52.5 Gy total) or standard CRT (median: 1.8 Gy fraction size, 54.5 Gy total). The primary endpoint was toxicity, and secondary endpoints were local failure and conversion to resectability. Comparisons were made using rank-sum or Fisher exact test and multivariable competing risk regression for the cumulative incidence of local failure. RESULTS: There were 28 patients in the nab-paclitaxel CRT group and 22 in the standard CRT group; 88% had the unresectable disease. The median follow-up was 18 months. The median duration of chemotherapy before concurrent CRT was 1.9 and 2.3 months in the nab-paclitaxel and standard CRT groups (P=0.337), and radiotherapy dose was 52.5 Gy (range, 52.5 to 59.4 Gy) and 54.5 Gy (range, 45.0 to 59.4 Gy), respectively. There were no statistically significant grade ≥2 toxicities. The nab-paclitaxel CRT group experienced a nonstatistically significant lower incidence of local failure (hazard ratio=0.91, 95% confidence interval: 0.27-3.03, P=0.536). More patients in the nab-paclitaxel CRT group proceeded to surgery (9/28 compared with 3/22 in the standard CRT, P=0.186); of which 6 (25%) in the nab-paclitaxel CRT and 2 (10%) in the standard CRT groups were initially unresectable. CONCLUSIONS: Nab-paclitaxel CRT had similar toxicity compared with standard CRT in the treatment of borderline resectable or unresectable pancreatic cancer. Its use was associated with an arithmetically lower cumulative incidence of local failure and an arithmetically higher conversion to resectability, both of which were not statistically significant.

Combining Stereotactic Body Radiotherapy and Microwave Ablation Appears Safe and Feasible for Renal Cell Carcinoma in an Early Series.

Microwave (MW) ablation and stereotactic body radiation therapy (SBRT) are both used in treating inoperable renal cell carcinoma (RCC). MW ablation and SBRT have potentially complementary advantages and limitations. Combining SBRT and MW ablation may optimize tumor control and toxicity for patients with larger (> 5 cm) RCCs or those with vascular involvement. Seven patients with RCC were treated at our institution with combination of SBRT and MW ablation, median tumor size of 6.4 cm. Local control was 100% with a median follow-up of 15 months. Four patients experienced grade 2 nausea during SBRT. Three patients experienced toxicities after MW ablation, 2 with grade 1 hematuria and 1 with grade 3 retroperitoneal bleed/collecting system injury. Median eGFR (estimated glomerular filtration rate) preceding and following SBRT and MW ablation was 69 mL/min/1.73 m2 and 68 mL/min/1.73 m2 (P = .19), respectively. In patients who are not surgical candidates, larger RCCs or those with vascular invasion are challenging to treat. Combination treatment with SBRT and MW ablation may balance the risks and benefits of both therapies and demonstrates high local control in our series. MW ablation and SBRT have potentially complementary advantages and limitations.

The efficacy and safety of definitive concurrent chemoradiotherapy for non-operable esophageal cancer.

OBJECTIVE: To report outcomes and toxicity in patients who received definitive concurrent chemoradiation (DCCRT) for non-operable esophageal cancer (EC) in the modern era, and to identify markers of overall and disease-free survival (OS/DFS). METHODS: We conducted a retrospective cohort study of patients with unresectable EC who received DCCRT at our institution between 1/2008 and 1/2019. Descriptive statistics were used to report disease-control outcomes and CTCAE v4.0-5.0 toxicities. Univariable and multivariable Cox regression, and stepwise regression were used to identify associations with survival. RESULTS: At a median follow-up of 19.5 months, 130 patients with adenocarcinoma (AC) (62%) or squamous cell carcinoma (SCC) (38%) were evaluable (Stage II-III: 92%). Patients received carboplatin/paclitaxel (75%) or fluorouracil-based (25%) concurrent chemotherapy. Median total RT dose was 50.4 Gy (range, 44.7-71.4 Gy) delivered in 28 fractions (24-35). Locoregional and distant recurrence occurred in 30% and 35% of AC, and 24% and 33% of SCC, respectively. Median OS and DFS were 22.9 and 10.7 months in AC, and 25.7 and 20.2 months in SCC, respectively. On stepwise regression, tumor stage, feeding tube during DCCRT, and change in primary tumor PET/CT SUVmax were significantly associated with OS and DFS. Most severe toxicities were acute grade 4 hematologic cytopenia (6%) and radiation dermatitis (1%). Most common acute grade 3 toxicities were hematologic cytopenia (35%), dysphagia (23%), and anorexia (19%). CONCLUSIONS: Treatment of non-operable EC with DCCRT has acceptable toxicity and can provide multi-year disease control for some patients, even in AC. Continued follow-up and investigation in large studies would be useful.

A Pilot Study of Galunisertib plus Stereotactic Body Radiotherapy in Patients with Advanced Hepatocellular Carcinoma.

TGFß is a pleiotropic cytokine with immunosuppressive activity. In preclinical models, blockade of TGFß enhances the activity of radiation and invokes T-cell antitumor immunity. Here, we combined galunisertib, an oral TGFß inhibitor, with stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC) and assessed safety, efficacy, and immunologic correlatives. Patients (n = 15) with advanced HCC who progressed on, were intolerant of, or refused sorafenib were treated with galunisertib (150 mg orally twice a day) on days 1 to 14 of each 28-day cycle. A single dose of SBRT (18-Gy) was delivered between days 15 to 28 of cycle 1. Site of index lesions treated with SBRT included liver (9 patients), lymph node (4 patients), and lung (2 patients). Blood for high-dimensional single cell profiling was collected. The most common treatment-related adverse events were fatigue (53%), abdominal pain (46.6%), nausea (40%), and increased alkaline phosphatase (40%). There were two instances of grade 2 alkaline phosphatase increase and two instances of grade 2 bilirubin increase. One patient developed grade 3 achalasia, possibly related to treatment. Two patients achieved a partial response. Treatment with galunisertib was associated with a decrease in the frequency of activated T regulatory cells in the blood. Distinct peripheral blood leukocyte populations detected at baseline distinguished progressors from nonprogressors. Nonprogressors also had increased CD8+PD-1+TIGIT+ T cells in the blood after treatment. We found galunisertib combined with SBRT to be well tolerated and associated with antitumor activity in patients with HCC. Pre- and posttreatment immune profiling of the blood was able to distinguish patients with progression versus nonprogression.

Proton beam re-irradiation for gastrointestinal malignancies: a systematic review.

BACKGROUND: Radiotherapy (RT) is part of the standard of care management of most gastrointestinal (GI) cancers. Even with advanced RT, systemic therapy, and surgical techniques, locoregional recurrences or second primary cancers can still occur within previously irradiated fields, which can present challenges in delivering effective and safe treatment. Options for reirradiation are often limited, but given the favorable dosimetric aspects of proton-beam RT, it may provide an effective and safe re-irradiation option for patients with recurrent or second primary GI cancers. METHODS: We conducted a systematic review as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol, assessing for reports of proton-beam reirradiation for recurrent or second primary GI cancers, primarily via PubMed. From the initial 373 articles identified, 7 articles were ultimately included in the analysis. RESULTS: The 7 included studies reported on proton-beam re-irradiation for the following disease sites: esophageal (n=2), pancreas (n=1), liver (n=2), rectal (n=1), and anal (n=1). Study sizes varied from as few as 1 to as many as 83 patients. Across studies, in patients who presented with tumor-related symptoms, palliation (stability/improvement) was achieved in 80-100% of the cases. Local control rates, with variable follow-up, ranged from 36-100%. All median overall survival values, when reported, were greater than 1 year. Across both liver studies, there were no cases of radiation-induced liver disease (RILD) from proton-beam re-irradiation. Across all studies, there were 2 acute (esophagopleural fistula in esophageal cancer, small bowel perforation in pancreatic cancer) and 1 late (esophageal ulcer in esophageal cancer) grade 5 toxicities, all favored to be due to progressive disease, rather than proton-beam re-irradiation. Two studies (1 esophageal, 1 rectal) generated comparison photon plans. One found that proton therapy reduced mean heart and lung doses, spinal cord dose, and lung V5Gy as compared to photon treatment, while resulting in higher lung V20Gy and V30Gy. The other found that protons decreased bowel V10Gy, V20Gy, and the dose to 200 and 150 cc of bowel, as compared to photons. CONCLUSIONS: Based upon the published experiences, proton-beam re-irradiation for recurrent or second primary GI cancers appears effective for palliation, with good disease-control, limited toxicity, favorable dosimetry, and overall compares well with published non-proton-beam experiences. Given short follow-up, additional studies are warranted to determine if dosimetric advantages from proton therapy will translate into comparative toxicity benefits.

Opportunity Costs of Receiving Palliative Chemotherapy for Metastatic Pancreatic Ductal Adenocarcinoma.

PURPOSE: The median overall survival (OS) for metastatic pancreatic ductal adenocarcinoma (mPDAC) is < 1 year. Factors that contribute to quality of life during treatment are critical to quantify. One factor-time spent obtaining clinical services-is understudied. We quantified total outpatient time among patients with mPDAC receiving palliative systemic chemotherapy. METHODS: We conducted a retrospective analysis using four patient-level time measures calculated from the medical record of patients with mPDAC receiving 5-fluorouracil infusion, leucovorin, oxaliplatin, and irinotecan; gemcitabine/nab-paclitaxel; or gemcitabine within the University of Pennsylvania Health System between January 1, 2011 and January 15, 2019. These included the total number of health care encounter days (any day with at least one visit) and total visit time. Total visit time represented the time spent receiving care (care time) plus time spent commuting and waiting for care (noncare time). We performed descriptive statistics on these outpatient time metrics and compared the number of encounter days to OS. RESULTS: A total of 362 patients were identified (median age, 65 years; 52% male; 78% white; 62% received gemcitabine plus nab-paclitaxel). Median OS was 230.5 days (7.6 months), with 79% of patients deceased at the end of follow-up. On average, patients had 22 health care encounter days, accounting for 10% of their total days survived. Median visit time was 4.6 hours, of which 2.5 hours was spent commuting or waiting for care. CONCLUSION: On average, patients receiving palliative chemotherapy for mPDAC spend 10% of survival time on outpatient health care. More than half of this time is spent commuting and waiting for care. These findings provide an important snapshot of the patient experience during ambulatory care, and efforts to enhance efficiency of care delivery may be warranted.

Comparative Effectiveness of Proton vs Photon Therapy as Part of Concurrent Chemoradiotherapy for Locally Advanced Cancer.

Importance: Concurrent chemoradiotherapy is the standard-of-care curative treatment for many cancers but is associated with substantial morbidity. Concurrent chemoradiotherapy administered with proton therapy might reduce toxicity and achieve comparable cancer control outcomes compared with conventional photon radiotherapy by reducing the radiation dose to normal tissues. Objective: To assess whether proton therapy in the setting of concurrent chemoradiotherapy is associated with fewer 90-day unplanned hospitalizations (Common Terminology Criteria for Adverse Events, version 4 [CTCAEv4], grade ≥3) or other adverse events and similar disease-free and overall survival compared with concurrent photon therapy and chemoradiotherapy. Design, Setting, and Participants: This retrospective, nonrandomized comparative effectiveness study included 1483 adult patients with nonmetastatic, locally advanced cancer treated with concurrent chemoradiotherapy with curative intent from January 1, 2011, through December 31, 2016, at a large academic health system. Three hundred ninety-one patients received proton therapy and 1092, photon therapy. Data were analyzed from October 15, 2018, through February 1, 2019. Interventions: Proton vs photon chemoradiotherapy. Main Outcomes and Measures: The primary end point was 90-day adverse events associated with unplanned hospitalizations (CTCAEv4 grade ≥3). Secondary end points included Eastern Cooperative Oncology Group (ECOG) performance status decline during treatment, 90-day adverse events of at least CTCAEv4 grade 2 that limit instrumental activities of daily living, and disease-free and overall survival. Data on adverse events and survival were gathered prospectively. Modified Poisson regression models with inverse propensity score weighting were used to model adverse event outcomes, and Cox proportional hazards regression models with weighting were used for survival outcomes. Propensity scores were estimated using an ensemble machine-learning approach. Results: Among the 1483 patients included in the analysis (935 men [63.0%]; median age, 62 [range, 18-93] years), those receiving proton therapy were significantly older (median age, 66 [range, 18-93] vs 61 [range, 19-91] years; P < .01), had less favorable Charlson-Deyo comorbidity scores (median, 3.0 vs 2.0; P < .01), and had lower integral radiation dose to tissues outside the target (mean [SD] volume, 14.1 [6.4] vs 19.1 [10.6] cGy/cc × 107; P < .01). Baseline grade ≥2 toxicity (22% vs 24%; P = .37) and ECOG performance status (mean [SD], 0.62 [0.74] vs 0.68 [0.80]; P = .16) were similar between the 2 cohorts. In propensity score weighted-analyses, proton chemoradiotherapy was associated with a significantly lower relative risk of 90-day adverse events of at least grade 3 (0.31; 95% CI, 0.15-0.66; P = .002), 90-day adverse events of at least grade 2 (0.78; 95% CI, 0.65-0.93; P = .006), and decline in performance status during treatment (0.51; 95% CI, 0.37-0.71; P < .001). There was no difference in disease-free or overall survival. Conclusions and Relevance: In this analysis, proton chemoradiotherapy was associated with significantly reduced acute adverse events that caused unplanned hospitalizations, with similar disease-free and overall survival. Prospective trials are warranted to validate these results.

The Evolving Use of Electronic Health Records (EHR) for Research.

Electronic health records (EHR) have been implemented successfully in a majority of United States healthcare systems in some form. There has been a rise in secondary uses of EHR, especially for research. EHR data is large, heterogenous, incomplete, noisy, and primarily created for purposes other than research. This presents many challenges, many of which are beginning to be overcome with the application of computer science artificial intelligence techniques, such as natural language processing and machine learning. EHR are gradually being redesigned to facilitate future research, though we are still far from a "complete EHR."